Beta-blockers in combination with ACE inhibitors are effective treating heart failure in patients with left ventricular systolic dysfunction. However, the mechanism of action is unclear.

To evaluate the biochemical role of beta-blockers in heart failure patients with left ventricular systolic dysfunction, investigators measured plasma renin activity and aldosterone concentrations among patients in an international, double blind, multicenter, randomized, parallel group trial. Investigators called this study Carvedilol Hibernation Reversible ISchaemia Trial: MArker of Success (CHRISTMAS).

The CHRISTMAS study included heart failure patients with left ventricular systolic dysfunction due to ischaemic heart disease and chronic stable heart failure (NYHA Class I, II, or III). About 60% of the patients had hibernating myocardium, regions of myocardium with reduced coronary perfusion that caused persistent left ventricular dysfunction. The main purpose of the study was to determine if presence of hibernating myocardium predicted degree of improvement in left ventricular ejection fraction.

All patients in CHRISTMAS received standard medications, including an ACE inhibitor, if they could tolerate them. Investigators randomized the patients to receive placebo or carvedilol for 6 months. There was a 2-month up-titration phase to the highest tolerated dose (6.25, 12.5, 25, or 50 mg bid), and an additional 4-month maintenance phase.

The intent-to-treat analysis included 305 patients (142 on carvedilol, 163 on placebo). The mean age was approximately 62 years and the mean ejection fraction at baseline was approximately 30%. ACE inhibitors were used by 87% of patients.

Investigators previously presented the main results of CHRISTMAS. For all patients, mean left ventricular ejection fraction rose on carvedilol compared with placebo (increase of 2.8% vs. decrease of 0.4%; p=0.0001). Importantly, they found a clear relationship between hibernating myocardium and improvement in left ventricular ejection fraction. There was a linear trend between change in left ventricular ejection fraction and number of myocardial segments with hibernation (p=0.009).

At the current meeting, Dr. Cleland reported on plasma renin activity from 242 patients in CHRISTMAS. Plasma renin activity tended to fall on carvedilol. The median change in plasma renin activity was a decrease of 38µU/mL for carvedilol vs. an increase of 2µU/mL for placebo. This trend approached statistical significance (p=0.054).

Investigators also had aldosterone concentration data for 188 patients. They found a trend toward reduced aldosterone concentrations on carvedilol. Aldosterone levels fell in the carvedilol group (median of 0.05 nmol/L), and remained unchanged in the placebo group (median 0.0 nmol/L). The difference between the carvedilol and placebo groups was not statistically significant.

Finally, they noted an inverse relationship between the fall in plasma renin activity and a rise in amino-terminal pro-brain natriuretic peptide. Although levels were essentially unchanged in the placebo group, they rose in the carvedilol group.

These results may help explain why the combination of carvedilol and an ACE inhibitor appears to offer a larger benefit than either agent alone. The ACE inhibitor can cause very large increases in renin, possibly weakening the effect of that drug. Carvedilol, however, may then significantly reduce plasma renin levels, and possibly further suppress aldosterone, as investigators showed in this study.